Project Summary/Abstract There is palpable excitement in the oncology community that we are on the cusp of a major advance in how we treat bladder (urothelial) cancer. Recent efforts to comprehensively define the landscape of genetic alterations in urothelial cancer and to understand their impact on drug sensitivity, as well as the exciting early results with immune targeting strategies suggest that prospective molecular profiling of blood and tumor tissue could improve the outcomes of urothelial cancer patients by personalizing care. This MSK SPORE in Bladder Cancer seeks to leverage recently initiated multicenter efforts to explore the molecular basis of inherited genetic susceptibility, exploit prospective molecular characterization to guide treatment, and to test the efficacy of immunotherapy-based combination approaches. The overall translational aims of the MSK SPORE in Bladder Cancer are to 1) develop predictive biomarkers of response and resistance to immunotherapy, chemotherapy, and investigational treatments; 2) identify germline genetic alterations that confer increased risk for the development of urothelial cancer; and 3) identify mechanisms of immunotherapy resistance and develop combinatorial strategies to enhance immunotherapy response in patients with urothelial cancer. To pursue these aims, we have assembled a multidisciplinary team with complementary expertise in the clinical management of urothelial cancer, inheritable risk, mycobacterial and cancer biology, cancer genetics, molecular pathology, biostatistics, computational biology, and multiplatform data integration. The translational aims of this SPORE will be pursued through four projects, each of which addresses a different clinical state in the evolution of the disease. Project 1 will use prospective molecular characterization to determine, in the context of a cooperative group trial, whether transurethral resection and chemotherapy, without the need for cystectomy, is curative in patients with DNA damage response gene alterations and to identify novel biomarkers of chemotherapy sensitivity. Project 2 will identify and functionally characterize novel germline variants that confer increased inherited susceptibility. Project 3 will seek to identify and validate tumor- and blood-based predictive biomarkers of response to systemic immune checkpoint blockade in patients with metastatic urothelial cancer in the context of a randomized, multicenter trial. Project 4 will seek to identify predictive biomarkers of Bacillus Calmette-Guerin (BCG) response and BCG strains with greater activity as a prelude to future clinical trials. Each of these projects will be supported by the Biospecimen Repository and the Biostatistics and Bioinformatics Core, which will assist with the preparation and analysis of human tissues and genomic, immune, and clinical data, and an Administrative Core will ensure project integration. Finally, developmental research projects and career mentorship are fully integrated into the SPORE to ensure that a future generation of researchers is prepared to further advance our long-term objectives of enhancing therapy, reducing the morbidity of treatments, and ultimately eliminating this disease as a cause of premature death.